The goals of this proposal are to develop robust, sensitive, and high throughput methods for mutation analysis for the tumor suppressor syndrome, tuberous sclerosis complex (TSC). These methods will be immediately useful for clinical purposes but will also be valuable research tools for analysing the molecular pathology in TSC and related disorders. The technology developed during this project will be directly applicable to the study of genetic variation in other disorders as well. TSC is a familial tumor syndrome characterized by the development of benign tumors (hamartomas) in multiple organs. Although it is inherited in an autosomal dominant pattern, the majority of new cases (about 65 percent) are sporadic without antecedent family history. Penetrance is high but expression is variable with both severely and mildly affected individuals. Organs most frequently involved are the brain, skin, kidneys and heart. Neurologic morbidity from seizures, mental retardation and behavior disorders is common. Two disease genes, TSC1 and TSC2 have been identified recently. Unfortunately the development of a genetic test has been hindered by the large size of the two genes and the diversity of the mutation spectrum in TSC. The R21 portion of this grant focuses on the development and optimization of a series of 3 assays which will allow for high throughput comprehensive genetic analysis for TSC. The R33 portion of this proposal focuses on using comprehensive mutation analysis for TSC to collect genotype and clinical data on a large cohort of TSC patients. Comprehensive mutation detection methods will also be used to study the role of TSC1 and TSC2 in related disorders as well as in TSC lesions and related non-TSC tumors. There is currently much demand from TSC patients and families for comprehensive mutation analysis for family planning and prenatal diagnosis, diagnosis confirmation, and prognostic information. The proposed plan of study will address this issue as well as help elucidate the role of TSC1 and TSC2 in the molecular pathology of TSC lesions and non-TSC tumors.
